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8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of nervous system disorders and cancer

a nervous system disorder and pyrimidin technology, applied in the field of 8ethyl6(aryl) pyrido2, 3dpyrimidin7 (8h)ones for the treatment of nervous system disorders and cancer, can solve the problems of cancer and nervous system disorders imposing an enormous health care burden on society, cancer and nervous system disorders are devastating to the quality of life of those affected and their families, can redu

Inactive Publication Date: 2014-06-12
AFRAXIS HLDG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes compounds that can improve cognitive functions and reduce symptoms associated with CNS disorders such as Alzheimer's disease. The compounds can be administered to individuals in need of treatment. The technical effects of the patent include improving neurological function and reducing atrophy or degeneration of nervous tissue in the brain.

Problems solved by technology

The effects of cancer and nervous system disorders are devastating to the quality of life of those afflicted as well as that of their families.
Moreover, cancer and nervous system disorders impose an enormous health care burden on society.

Method used

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  • 8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of nervous system disorders and cancer
  • 8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of nervous system disorders and cancer
  • 8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of nervous system disorders and cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 6-(2-chloro-4-[1,3,4]oxadiazol-2-yl-phenyl)-8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (8)

Preparation of Intermediate Compounds

Intermediate 1: Synthesis of 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3)

[0693]

Step 1: Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2)

[0694]To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1, 1.00 g, 5.18 mmol) in anhydrous dimethylformamide (25 mL) was added N-bromosuccinimide (0.99 g, 5.59 mmol) portionwise at room temperature, and the reaction mixture was stirred for 18 h. The mixture was concentrated, and the solid was triturated with hot water (1×20 mL), filtered, and washed with isopropanol to give title compound as a pale yellow solid (0.68 g, 2.50 mmol, 48%). ESMS m / z 272 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H), 8.84 (s, 1H), 8.47 (s, 1H), 2.57 (s, 3H).

Step 2: Synthesis of 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]py...

example 2

Synthesis of 6-[2-chloro-4-(thiophen-2-yl)phenyl]-8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (13)

[0702]

Preparation of Intermediate Compounds

Intermediate 2: Synthesis of ethyl 4-bromo-2-chlorophenylacetate (19)

[0703]

Step 1: Synthesis of (4-bromo-2-chlorophenyl)methanol (15)

[0704]4-Bromo-2-chlorobenzoic acid (14, 92.0 g, 0.39 mol) was dissolved in dry tetrahydrofuran (920 mL) and cooled to −15° C. Isobutyryl choroformate (51.0 mL, 0.39 mol) was added followed by N-methylmorpholine (43.5 mL, 0.39 mol). The resulting mixture was stirred for 10 minutes at −15° C., cooled to −25° C. and the precipitated N-methylmorpholine hydrochloride salt was filtered off. The filtrate was warmed to −5° C. and a solution of sodium borohydride (22.19 g, 0.586 mol) in water (190 mL) was added dropwise to the mixture keeping the temperature below 0° C. After stirring for 1 h at 0° C., the volatiles were evaporated, and the residue was diluted with water (500 mL) and d...

examples 3-4b

[0716]The following compounds were made by the method of Example 2 using the appropriate arylacetic ester at Step 1 and aniline at Step 3. Examples containing secondary amines on the aniline were synthesized using the appropriate Boc protected aminoaniline and in the final step were treated with a solution of hydrogen chloride in an organic solvent to produce the example compound, usually isolated as the hydrochloride salt. In this manner, Example 3 was prepared using methyl 2-[5-methyl-2-(n-tert-butoxycarbonylpiperidine)-1,3-thiazol-4-yl]acetate and 4-(4-methylpiperazino)aniline. Example 4a and Example 4b were prepared from Example 3 by reductive methylation and treatment with acetic anyhydride respectively.

LCMSLCMSEx.StructureMWMethodIonRt3544.7B5450.964a558.8B5600.984b586.8B5871.16

Examples 5-9

Preparation of Intermediate Compounds

Synthesis of 2-(4-Amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (25)

[0717]

Step 1: Synthesis of 2-(4-nitro-phenyl)-oxirane (21)

[0718]To an i...

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Abstract

Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders or neurofibromatosis. Also described herein are methods of utilizing PAK inhibitors for the treatment of cancer.

Description

CROSS-REFERENCE[0001]This application claims the benefit of U.S. provisional application Ser. No. 61 / 473,683, filed Apr. 8, 2011; which is incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Nervous System disorders are characterized by a variety of debilitating affective and cognitive impairments and can be classified as central nervous system (CNS) disorders and peripheral nervous system (PNS) disorders.[0003]Neurofibromatosis type 1 (NF1) affects nerves of the peripheral nervous system. A neurofibroma is a benign nerve sheath tumor in the PNS and can result in a range of symptoms from physical disfiguration and pain to cognitive disorder. Neurofibromatosis type 2 (NF2) affects the CNS and can cause tumors in the brain and spinal cord.[0004]Cancer, also called malignancy, is characterized by an abnormal growth of cells. There are more than 100 types of cancer, including breast cancer, skin cancer, lung cancer, colon cancer, brain cancer, prostate cancer, kid...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04
CPCC07D471/04C07D519/00A61K45/06A61K9/0014A61K9/0019A61K9/0031A61K9/0043A61K9/0048A61K9/0056A61K9/0078A61K9/06A61K9/2054A61K9/4866A61P25/00A61P25/18A61P25/24A61P25/28A61P35/00A61P35/02A61P43/00A61K31/519
Inventor CAMPBELL, DAVIDDURON, SERGIO G.
Owner AFRAXIS HLDG
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